Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of a series of adhesion receptors: L-selectins (CD62L): Leu-8, several integrins (LFA-1: CD11a/CD18, VLA-4: CD49d/CD29 and VLA-5: CD49e/CD29), ICAM-1(CD54) and the 'homing receptor' (CD44) were investigated by a dual color flow cytometry in 56 cases of B cell disorders namely, 39 chronic lymphocytic leukemias (CLL), four hairy cell leukemia (HCL), seven splenic lymphoma with villous lymphocytes (SLVL) and six other non-Hodgkin's lymphoma (NHL). The functional activity of L-selectins was assessed with L-selectin ligand analogs (polyphosphomonester core polysaccharide: PPME and fucoidin). Leukemic B cells were identified with phycoerythrin-conjugated monoclonal antibodies (McAbs) anti-CD19, anti-kappa/lambda investigated simultaneously for the expression of adhesion receptors estimated with fluorescein-isothiocyanate (FITC) conjugated McAbs. The percentage of leukemic cells expressing L-selectins (Leu-8) was high in CLL (52% of positive cases) and integrin expression (LFA-1, VLA-4, 5) was low (19 and 33%, respectively), while a reverse pattern, low Leu-8 (17%), and a high VLA-4 (77%), was observed in non-CLL cases. The expression of LFA-1 alpha-chain was variable in non-CLL cases, and the LFA-1 heterodimer was expressed on most clonal B cell in NHLs (92%). LFA-1 alpha-chain was detected on cells from only one HCL case, while beta2 integrin was regularly expressed on hairy cells. VLA-5 integrin was found on a relatively small number (26%) of mature B cell leukemias. A remarkable finding was the detection of ICAM-1 in all CLL cases albeit the number of positive cells was significantly lower (P < 0.05) compared to non-CLL cases. CD44 was expressed on a high number of neoplastic cells in all the investigated categories. There was no correlation between the expression of the adhesion molecules and clinical and laboratory parameters except for CD18 which was expressed on a significantly (P < 0.05) higher number of leukemic cells in CLL with more advanced stages. This study demonstrates that even closely related B cell leukemia/lymphomas have a certain well defined and strictly variable adhesion profile which is characteristic of the disease entity and therefore, the adhesion profile may offer additional information useful for differential diagnosis and study of disease pathogenesis.
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PMID:Adhesion receptors on peripheral blood leukemic B cells. A comparative study on B cell chronic lymphocytic leukemia and related lymphoma/leukemias. 906 81

The availability of monoclonal antibodies with well-defined specificities to lymphoma-associated antigens promises to open new therapeutic opportunities in the treatment of patients with non-Hodgkin's lymphoma. Monoclonal antibodies against lineage-specific surface markers such as CD19, CD20 or CD22 have been generated and employed in native or modified forms in clinical phase I/II trials. Modified versions such as toxin-conjugated antibodies or antibodies with dual specificities (bispecific antibodies) were introduced to enhance the cytotoxicity of monoclonal antibodies since native antibodies were not able to induce long-lasting remissions in patients with advanced disease although responses were seen and side-effects were usually mild. Future efforts should concentrate on patients with minimal residual disease employing genetically engineered antibody fragments.
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PMID:Monoclonal antibodies in the treatment of non-Hodgkin's lymphoma: recent results and future prospects. 917 42

The severe combined immunodeficient (SCID) mouse model is an important tool with which to study new strategies for treating hematologic neoplasia. For these experiments, a large number of human cell lines growing in SCID mice are a prerequisite. We describe a new Epstein-Barr virus (EBV)-positive B cell line, designated BEVA, with a complex karyotype including translocations t(14:18)(q32;q21) and t(4;11) (q21;q23) that meets this need. As demonstrated by Southern blot analysis, BCL2 at 18q21, but not MLL/ALL1 at 11q23, was involved in these translocations. BEVA cells coexpressed lymphoid (IgG-kappa, CD19, CD20, CD21, and CD24) and myeloid (CD11b, CD15, and CDw65) markers. Interestingly, the cell line was established from the bone marrow culture of a patient with acute myeloid leukemia (AML). Examination of bone marrow biopsy specimens suggested the presence of non-Hodgkin's lymphoma (NHL) in this patient in addition to AML. In vitro and in vivo growth characteristics of the BEVA cell line were compared with the previously described EBV-positive B cell line DoHH2, also carrying a translocation t(14;18)(q32;q21). These DoHH2 cells additionally expressed CD10, whereas, in contrast to BEVA cells, only a small population of DoHH2 cells showed expression of CD44. Both cell lines showed similar growth characteristics in vitro, but reacted differently to cytokines, including interleukin (IL)-4, IL-6, IL-7, and alpha-interferon (IFN). Upon inoculation in SCID mice, marked differences were observed in the dissemination patterns of the BEVA or DoHH2 cells. Although both cell lines circulated in the blood and were predominantly found in murine bone marrow and lymphoid tissues, DoHH2 cells infiltrated the murine spleens, whereas BEVA cells could only rarely be detected in these tissues. In contrast to DoHH2 cells, BEVA cells gave rise to tumor masses in liver, kidney, and para-aortal or mesenteric lymph nodes. The relationship between these in vitro differences and the observed differences in dissemination of both cell lines is discussed.
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PMID:Characterization of a novel malignant B cell line with t(14;18) and t(4;11) established from a patient with acute monoblastic leukemia. 929 3

A major obstacle in purifying either autologous or allogeneic hematopoietic stem cells from granulocyte colony-stimulating factor (G-CSF) mobilized circulating progenitor cells (CPC) is represented by the huge cellularity present in each apheretic product. To obtain a significant debulking of unwanted cells from the leukapheresis, we developed a modified protocol of immune rosetting whereby human ABO-Rh- compatible red blood cells (RBCs) are treated with chromium chloride and then coated with murine monoclonal antibodies (MoAbs) against leukocyte antigens. When experiments were performed with leukaphereses obtained from normal donors or from T-cell acute lymphoblastic leukemia (T-ALL) patients, RBCs were coated with murine MoAbs against human mature myeloid cells (CD11b) and T cells (CD6); whereas, in the case of patients with B-precursor ALL, B-cell non-Hodgkin's lymphoma (B-NHL), or multiple myeloma (MM), RBCs were coated with anti-CD11b only. After incubation with CPC, rosetting cells (myeloid precursor cells, granulocytes, monocytes, and T cells) were removed by Ficoll-Hypaque density gradient centrifugation with a blood cell processor apparatus, COBE (Lakewood, CO) 2991. After this step, a significant reduction of the initial cellularity was consistently obtained (range, 72% to 97%), whereas the median absolute recovery of the CD34+ cells was above 85% (range, 64 to 100), with a 10-fold relative enrichment ranging from 3% to 41%. In a second step, CPC can be further purged of contaminating T or B cells by incubation with lymphoid-specific magnetic microbeads (anti-CD2 and -CD7 to remove T cells; anti-CD19 to remove B cells) and elution through a type-D depletion column (composed of ferromagnetic fiber) inserted within a SuperMACS separator device (Miltenyi Biotech, Bergisch-Gladbach, Germany). By this approach, a highly effective (three to four logs) T-cell depletion was achieved in all experiments performed with normal donors or T-ALL patients (median loss of CD3+ cells: 99.8% [range 99.2 to 100]) and an equally efficient B-cell depletion was obtained from B-precursor ALL, B-NHL, or MM patients. At the end of the procedure the T- or B-cell depleted fraction retained a high proportion of the initial hematopoietic CD34+ stem cells, with a median recovery above 70% (range 48% to 100%) and an unmodified clonogenic potential. In five patients (two follicular NHL and three ALL) the purified fraction of stem cells was found disease free at the molecular level as assessed by polymerase chain reaction (PCR) analysis of the t(14;18) chromosome translocation or clono-specific DNA sequences of IgH or T-cell receptor gamma and delta chain genes. Purified autologous and allogeneic CPCs were transplanted in three and six patients, respectively, who showed a prompt and sustained hematologic engraftment. In conclusion, this method represents a simple and reproducible two-step procedure to obtain a highly efficient purging of T or B cells from G-CSF expanded and mobilized CPCs. This approach might lead to the eradication of the neoplastic clone in the autologous stem cell inoculum as well as for T-cell depletion during allogeneic transplantation.
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PMID:Innovative two-step negative selection of granulocyte colony-stimulating factor-mobilized circulating progenitor cells: adequacy for autologous and allogeneic transplantation. 949 Jul 8

Reinfusion of residual tumor cells into B cell non-Hodgkin's lymphoma (B-NHL) patients during autologous transplantation may be an important cause of disease relapse. Determining the extent to which B-NHL cells are present in autologous progenitor cell products and if the presence of residual B-NHL cells is predictive of relapse will require extremely sensitive methods of detecting rare B-NHL cells. We attempted to improve the sensitivity of polymerase chain reaction (PCR)-based detection of rare B-NHL cells by preselecting CD19+ cells using an immunomagnetic column. To measure detection sensitivity, we prepared samples containing different levels of B-NHL cell contamination by mixing B-NHL cell lines containing the chromosomal translocation t(14;18) bcl-2/JH) with control leukapheresis samples. DNA extracted from each CD19-selected sample and from each matched nonselected sample was added to a PCR to amplify the bcl-2/JH breakdown junction. CD19 preselection improved the sensitivity of detection of t(14;18)-positive B-NHL cells 115-fold, so that B-NHL cells at a concentration of 1 tumor cell per 1 x 10(6) hematopoietic cells were detected in every specimen evaluated. t(14;18)-positive cells were not detected in any of 13 control leukapheresis specimens. We conclude that a combination of CD19 preselection and PCR amplification may improve the sensitivity of detection of rare lymphoma cells by two orders of magnitude without a significant decrease in specificity.
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PMID:CD19 selection improves the sensitivity of B cell lymphoma detection. 959 73

The PAX5 gene encodes the BSAP (B-cell-specific activator protein) which is a key regulator of B-cell development and differentiation. A recurring translocation t(9;14)(p13;q32) in non-Hodgkin's lymphoma moves the PAX5 on 9p13 within close proximity of the immunoglobulin heavy chain gene (IGH). KIS-1 cell line was established from a patient with diffuse large cell lymphoma of B-cell type carrying t(9;14). We analysed PAX5/BSAP expression by Northern and Western blotting in a panel of haematological tumour cell lines with other chromosome abnormalities in comparison with that of KIS-1. PAX5 mRNA and BSAP expression were detected in all B-cell lines tested, and the high level in KIS-1 was confirmed. However, a diffuse large B-cell lymphoma cell line and an acute B-lymphoid/myeloid leukaemia cell line expressed the PAX5/BSAP at levels comparable with KIS-1. PAX5 transcripts were readily detectable in clinical materials with a wide variety of B-cell neoplasms by reverse transcriptase-mediated polymerase chain reaction (PCR). Thus, PAX5/BSAP activation in haematological tumour cells is not necessarily associated with t(9;14). Although binding sites for BSAP have been identified in the promoters of CD19, this study failed to find clear correlation between the level of PAX5/BSAP expression and that of CD19. In contrast to KIS-1 in which the E mu enhancer of IGH was juxtaposed to PAX5, cloning of t(9; 14) from another case by long-distance PCR revealed that the PAX5 promoter was linked to a Cgamma constant region in divergent orientation, suggesting that the mechanism of PAX5 activation through recombination with IGH varies among individual cases. Breakpoints on 9p13 of the two translocations were clustered upstream of PAX5, leaving the PAX5 coding region intact.
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PMID:Expression of the PAX5/BSAP transcription factor in haematological tumour cells and further molecular characterization of the t(9;14)(p13;q32) translocation in B-cell non-Hodgkin's lymphoma. 972 95

Immunotoxins, composed of a monoclonal antibody conjugated to a protein toxin, mediate cell death through novel cytotoxic mechanisms. Anti-B4-blocked ricin (anti-B4-bR) recognizes CD19-positive cells, which includes most B-cell non-Hodgkin's lymphomas (NHLs). Previous Phase I clinical studies of anti-B4-bR, using both bolus and continuous dosing regimens, demonstrated no safety or efficacy advantage to the continuous infusion regimen. This Phase II trial in 16 patients with relapsed CD19-positive NHL was conducted to evaluate the efficacy of anti-B4-bR when administered at the previously established maximum tolerated dose using a daily bolus for a 5 consecutive days schedule. Serum pharmacokinetics were measured in selected patients. Tissue samples of involved lymph nodes and bone marrow were also obtained from a portion of patients for determination of anti-B4-bR penetration into tissues. Toxicity was similar to what has been described previously for anti-B4-bR and consisted mainly of reversible elevations of hepatic transaminases and mild to moderate thrombocytopenia. No sustained clinical responses were documented. Pharmacokinetic measurements demonstrated that serum levels compatible with 3 logs of cell kill in vitro could be sustained for several hours in most patients. Immunohistochemical analysis of tissue samples provided some insight into the low efficacy. The immunotoxin could be detected in three of the four bone marrow aspirate samples but in only two of the seven lymph node specimens. Thus, anti-B4-bR, using a single daily bolus for a 5 consecutive day schedule, is not an active agent in relapsed NHL. Poor penetration into certain sites of disease may be one explanation for its lack of efficacy.
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PMID:Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin's lymphoma. 982 22

Patients with unexplained cytopenias often present a diagnostic dilemma with minimal morphologic or cytogenetic changes to identify the underlying disease process. We have used multidimensional flow cytometry in a study of patients with cytopenias and found that this technology established, changed, or refined the diagnosis in 17/121 patients. Using the flow cytometric technique of CD45 and right angle light scatter (SSC) gating with two additional markers in a three-color analysis, eight of 121 patients were found to have hairy cell leukemia (HCL), in the absence of definitive morphologic findings of HCL. Two additional patients were found to have non-Hodgkin's lymphoma (NHL). Myeloid abnormalities, myelodysplasia (MDS) or acute leukemia was detected in seven of 56 patients with unexplained pancytopenia. Six of 65 patients identified with cytopenias resulting from lymphoid neoplasms had been referred for bone marrow transplantation (BMT) with a presumptive diagnosis of MDS, with subsequent deferral of BMT upon correct diagnosis. The screening technique is incorporated into an extensive immunophenotyping scheme to identify hematopoietic abnormalities using multidimensional flow cytometry (MDF). HCL cells (detected as low as 1.3%) reside in the same position as normal monocytes in the CD45 and SSC plots but could be distinguished from monocytes based on the expression of HLA-DR without CD11b, and expression of CD19. Further phenotyping of the abnormal population confirmed immunoglobulin light chain restriction, CD11c, and CD25 expression. Non-Hodgkin's lymphoma was detected as aberrant mature lymphocytes expressing B lymphoid markers, CD5 and light chain restriction. Myeloid abnormalities were identified in the myeloblast or maturing myeloid cell fractions. The flow cytometric scheme described can be used in primary diagnosis. The technique is definitive, sensitive, and stresses the importance of distinguishing lymphoid from myeloid etiology of cytopenias.
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PMID:Occult B cell malignancies can be detected by three-color flow cytometry in patients with cytopenias. 984 32

We conducted a double retroviral vector (RV) gene marking trial to test for the possible contribution to relapse of follicular non-Hodgkin's lymphoma (FNHL) cells present in bone marrow (BM) and peripheral blood (PB) grafts used for hematopoietic reconstitution of patients undergoing myelaoblative chemotherapy and autologous transplant. CD34 positive selection using the CellPro Ceprate CD34 column was performed on PB mononuclear cells obtained after cyclophosphamide/G-CSF mobilization. CD34 positive cells were exposed for 4-6 hours to the LNL6 or G1 Na RV in the absence of growth factors or stromal monolayers. One week later, BM mononuclear cells were similarly processed. Patients then received total body irradiation (TBI), cyclophosphamide, and etoposide followed by infusion of both PB and BM CD34 positive cells. Semiquantitative Southern blot analysis of DNA t(14;18) amplification products showed approximately a three log reduction in t(14;18) positive cells after CD34 positive selection. The first patient showed evidence of engraftment with RV positive BM and PB cells for 9 months. He relapsed one year after transplant. At relapse, one year after transplant, he had lost evidence of RV positive cells in ficolled mononuclear BM and PB cells as well as in CD19 positive cells. The second and third patients showed evidence of engraftment with RV positive cells up to 9 and 6 months post BMT respectively. The second and third patients are still in clinical remission. Our results demonstrate engraftment of RV transduced hematopoietic cells in the PB and BM for up to 9 months.
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PMID:Hematopoietic retroviral gene marking in patients with follicular non-Hodgkin's lymphoma. 1003 25

Rituximab is a chimeric antibody with human gamma-1 and kappa constant regions and murine variable regions. It recognizes the CD20 antigen, a pan B-cell marker. Therapeutic trials in patients with B-cell non-Hodgkin's lymphoma (NHL) have shown significant efficacy with a primary response rate of 50%, and a secondary response rate of 44% after repeat treatments in prior responders. The selection for proliferating tumor cells that no longer express CD20 may compromise repeated treatment. We have identified a patient who developed a transformed NHL that lost CD20 protein expression after two courses of therapy with rituximab. In a pretreatment lymph node biopsy, 83% of B cells (as defined by CD19 and surface immunoglobulin) expressed surface CD20. A biopsy from the recurrent tumor after two courses of rituximab revealed a diffuse large cell NHL where 0% of B cells expressed CD20 with no evidence of bound rituximab. Cytoplasmic staining showed no CD20 protein. Sequencing of immunoglobulin heavy chain cDNA identified identical variable sequences in the initial and recurrent lymphomas, confirming the association between the two tumors. Literature and database review suggests that approximately 98% of diffuse large cell lymphomas express CD20, which suggests that these tumors rarely survive without CD20. This is the first identified case of loss of CD20 expression in a lymphoma that has relapsed after rituximab therapy, although several other cases have since been identified. Considering the significant number of patients treated with anti-CD20 antibodies, this may occur only rarely and is unlikely to preclude recurrent therapy with anti-CD20 antibodies in the majority of patients. However, because many patients have relapsed after anti-CD20 antibody therapy and have not been biopsied to identify clones with down-regulated CD20 antigen, we do not currently know the true frequency of this phenomenon. When possible, patients should undergo evaluation for CD20 expression before repeated courses of anti-CD20 therapy.
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PMID:Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. 1065 64


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